The goal of this application is to develop an F-18 labeled PET radiotracer to image the serotonin transporter (SERT) in discrete brain areas, especially areas with low density of SERT. The SERT, located on the cell bodies and terminals of the 5-HT neurons, is a marker of 5-HT innervation. Alterations in 5-HT transmission and SERT densities have been described in a number- of neuropsychiatric conditions, including major depression, anxiety disorders, schizophrenia, drug abuse, alcoholism, eating disorders, Alzheimer's and Parkinson's disease. The currently available PET radiotracer, [11C](+)-McN5652, suffers from many limitations, including high levels of nonspecific binding, poor in vivo signal to noise ratio, and slow brain kinetics. Due to these drawbacks, [11C](+)-McN5652 can only be used to image the brain regions with high SERT densities (midbrain, thalamus and striatum), but not those with lower SERT densities, such as hippocampus, amygdaIa and neocortex, where localized alterations in SERT densities have been identified in postmortem studies. In this application we propose to develop a new ligand, 2-[2-(dimethylaminomethyl) phenylsulfanyl)]-5-fluoromethylphenylamine, or AFM, into a PET ligand. AFN is a potent and selective SERT ligand that can be radiolabeled with either C-11 or F-18. Preliminary results indicate that [11C]AFM possesses high affinity and excellent binding specificity in vivo. Imaging studies in baboons demonstrates that [11CIAFM is a PET tracer with superior imaging properties, including faster kinetics and a higher signal-to-noise ratio compared to [11C](+)-McN5652. These characteristics make it possible to image brain regions with low SERT densities. We propose to develop [ 11C]AFM and [18F]AFM for clinical imaging applications. Experiments are designed to: 1) characterize fully the in vivo pharmacology and pharmacokinetics of [11C]AFM and [18F]AFM; 2) assess the potential and suitability of [11C]AFM and [18F]AFM to image the SERT in brain regions of both high and low SERT densities; and 3) characterize the imaging properties of [11C]AFM and [18F]AFM in healthy human subjects. The ultimate goal is to introduce [11C]AFM and [18F]AFM into the clinics to probe the role of SERT in neuropsychiatric disorders. Introduction of [18F]AFM would constitute the first PET tracer for the SERT that can be prepared in a central facility and distributed to various sites for clinical imaging purposes.